1. Technical Field
The present invention relates, in general to anti-viral therapy, and, in particular, to a method of inhibiting viral production which involves the use of the cytokine, leukoregulin.
2. Background Information
Herpesvirus infections are responsible for a wide spectrum of acute and recurrent diseases affecting millions of individuals throughout the world (Johnson et al, N. Engl. J. Med. 1989, 321:7-12; Corey et al, N. Engl. J. Med. 1986, 314:686-91, 749-57). The need for effective drug treatment and prevention of herpesvirus and other viral diseases has assumed growing importance. The increasing prevalence of AIDS and HIV associated infections, in addition, has stimulated a renewed interest in antiviral chemotherapy (Crumpacker, N. Engl. J. Med. 1989, 321:163-172).
During the past five years it has become clear that a single mode of therapy for virus infections may not be as effective as combination therapy. Major support for this conclusion is the development of cytokines and other "biological response modifiers" in the combined use of chemotherapy to treat various malignancies (Foon, Can. Res. 1989, 49:1621-39). With this background, studies were initiated to determine if a new cytokine, leukoregulin, which increases drug uptake in cancer cells might be useful to enhance anti-viral chemotherapy. (See U.S. Pat. No. 4,849,506.) Since acycloguanosine (ACG; 9-(2-hydroxyethoxymethyl)guanine) is active against human herpesviruses both in vitro and in vivo, ACG inhibition of acute herpesvirus production was selected as a model system to test the ability of leukoregulin to enhance anti-viral chemotherapeutic action (Elion, New Directions for Clinical Application and Research in Antiviral Chemotherapy. J. Mills & L. Corey, Eds. (Elsevier, New York, 1986) pp 118-137; Elion, Sci. 1989, 244:41-47; Crumpacker et al, Antimicrobiol. Agents & Chem. 1979, 15:642-645; and Erlich et al, N. Engl. J. Med. 1989, 320:293-6).
Leukoregulin, first described in 1984, is a lymphokine possessing unique regulatory activities for transformed cells (Ransom et al, Cancer Res. 1985, 45:851-862; Evans, Leukoregulin mechanisms of anticancer action. In Leukolysins and Cancer (Ransom, J. H., Ortaldo, J. R. eds.) The Humana Press, Inc., Clifton, N.J. 1988, pp 198-216). Today, it is apparent that this cytokine has a multifunctional nature which is reflected in the variety of its biologic activities. Leukoregulin can prevent chemical carcinogen transformation, inhibit neoplastic cell proliferation and augment target cell sensitivity to natural killer (NK) cell cytotoxicity (Evans, Leukoregulin mechanisms of anticancer action. In Leukolysins and Cancer (Ransom, J. H., Ortaldo, J. R. eds.) The Humana Press, Inc., Clifton, N.J. 1988, pp 198-216). More recently, this cytokine has been shown to increase membrane permeability of tumor cells and to increase drug uptake (Barnett et al, Cancer Res. 1986, 46:2686-92; Evans et al, J. Nat. Cancer Inst. 1988, 80:861-4). The ability of leukoregulin to enhance drug uptake occurs concomitantly with the increase in membrane permeability in tumor cells but not in normal cells.
It will be clear from a reading of the disclosure that follows that leukoregulin enhances membrane permeability of cells acutely infected with virus. This represents a hitherto unrecognized biological role for leukoregulin i.e., its ability to recognize and alter acutely virally infected cells. Treatment with leukoregulin can, therefore, be used to target entry of pharmacologically active agents into virus infected cells. The permeableness of virus infected-cells and associated enhanced drug effectiveness provides an alternative approach to the targeting of drugs for infections induced by viruses such as papillomavirus, cytomegalovirus and the human immunodeficiency virus (HIV).
The present invention thus provides a method of treating viral infection which, in one embodiment, is based on the combined use of immunotherapy (specifically, leukoregulin therapy) and anti-viral chemotherapy.